(Revised 2/24/03) Insect-borne infectious diseases such as malaria affect at least 1 billion people worldwide, and over 1.5 million of these infected individuals die each year. Malarial parasites and many other vector-borne pathogens have developed resistance to current drugs, and vaccines are not available or feasible for many of these pathogens. Insect vector control programs have historically been an effective strategy for reducing disease transmission. However, some of these diseases have remained intractable while others have become resurgent. For this proposal, Cambria Biosciences, an innovative applied genomics biotechnology company, intends to exploit genetically validated insect targets for lead compound discovery, with the ultimate aim of discovering new environmentally sound and effective insecticides that can be incorporated into integrated insect vector management programs for public health. In highly informative preliminary studies at Cambria, comparative genomic analysis has identified insect members of the glutamate neurotransmitter signaling pathway. In insects, glutamate is the primary excitatory neurotransmitter at the neuromuscular junction and plays a major signaling role within the central nervous system. Genetic screens in the model insect Drosophila melanogaster have identified multiple mutations in the glutamate signaling pathway that confer a rapid knock-down phenotype that mimics the effects of commercially successful insecticides. These results provide genetic validation for exploiting this pathway for small molecules that will disrupt insect neuronal function and organismal viability by selectively interfering with insect glutamatergic signaling pathways. The specific aim for Phase I (Years 1-2) of this project is functional expression of selected insect protein targets in the glutamate signaling pathway, initially from Drosophila followed by Anopheles, in transformed cells suitable for high-throughput screening. Subsequent specific aims for Phase II (Years 3-4) will be to implement pilot and large-scale chemical screens for active compounds. This combination of state-of-the-art dipteran genomics and high-throughput chemical screening is a highly promising multidisciplinary approach for discovering and developing new products that are desperately needed for the global control of human disease vectors.